(W1230-09-57) Innovative Formulation Strategies for orodispersible Loratadine Dosage Forms

Purpose: Pediatric drugs have unique formulation requirements designed to help ensure patient safety while facilitating compliance and adherence to the prescribed medication schedule. The use of well-established and safe excipients with the required quality and supporting documentation is essential for successful development and manufacturing of these drugs and to minimize risk for highly vulnerable patients. In addition, there are high demands on patient compliance: for example, palatability must be addressed during the development process, and optimized child-friendly dosage forms are required that enable an accurate dosing. Loratadine, an antihistamine medication, is widely prescribed for the treatment of various allergic conditions in pediatric patients because of its efficacy in the treatment of allergic disorders. Considering the unique physiological and psychological needs of children, kids-friendly orodispersible mini-tablets and films were developed. The API Loratadine is classified as a class II drug based on the Biopharmaceutical Classification System due to its low water solubility [1]. To increase the low solubility, it was aimed to produce orodispersible films by hot melt extrusion - a solvent-free process which, through heating and mixing, disperses the API with a matrix polymer, helping to increase the dissolution rate and improving the solubility.

Methods: Orodispersible mini-tablets (ODMTs, 3 mm): produced by wet granulation with low shear mixer (Planetary mixer N50/ Hobart with peristaltic pump Pumpdrive 5201/ HeidolphTM; speed 136 rpm, flow rate 10 g/min; drying process in vacuum oven (Thermicon/Heraeus); vacuum: 200 mbar, temp.: 50°C, drying time: 20 h). A free-fall mixer is used for the tableting mixture (Turbula® T2A/Willy A. Bachofen AG; mixing time: 5 min, screw speed: 47 rpm). For tableting, a single punch press is used (STYL’One Evo/MEDELPHARM; pressure: 1.7 kN, speed: 10%). The tablets are characterized by diameters, tensile strength, tablet hardness (MultiCheck ERWEKA, n=20), disintegration time (DISI4 BIOMATION; n=6, Limit Ph.Eur. < 180 s; USP < 30 s) and dissolution performance of API in simulated gastric fluid, pH 1.2, SOTAX Xtend ^TM dissolution tester; n=6). Formulation: Loratadine (50% w/w), mannitol-based ODT excipient system (46% w/w), magnesium stearate (1% w/w), polyvinyl alcohol (PVA) 4-88 (0.9% w/w), SiO2 (0.5% w/w) and neotame (0.06 % w/w). Orodispersible films (ODFs): produced by hot melt extrusion technology (twin-screw extruder connected with sheet take-off unit/Thermo Scientific is used, extruding temp.: 190 °C, screw speed: 500 rpm). The pre-mixed powder of Loratadine and particle engineered PVA 4-88 (Parteck® MXP 4-88 Polymer) is continuously fed into the Thermo Process HYG extruder feeder by using the twin-screw feeder, and triacetin is continuously fed into the extruder by peristaltic pump after the feeding port of powder feeding. Set up the feeding speed of solid material (mixture of PVA 4-88 and Loratadine) and liquid material (triacetin) at about 9:1. The films are characterized by diameters, weight, disintegration time  in 900 ml water (ERWEKA ZT 322; n=3), clamping top center of the film with slow swing, small scale test run and dissolution performance in 500 ml simulated saliva (pH 6.7) with 0.6% polysorbate 80 (ERWEKA DT 828,; n=3) at 37°C (USP Type II). Formulation: Loratadine (7.5% w/w), PVA 4-88 (82.47% w/w), triacetin (10% w/w), neotame (0.03% w/w)

Results: Robust and hard ODMTs are obtained (figure 1). The measured average disintegration time of 78 ± 7 s in DI water is meeting the requirements of Ph. Eur. that specifies a disintegration time of below 180 s for ODTs. A fast drug release is achieved in simulated gastric fluid which is comparable with the release time of a commercial drug product. Tablet parameters: Ø 3 mm tablets with 5 mg API, tablet weight 10 mg, tablet hardness 19 N. For the ODFs, a smooth processibility is recognized, and homogeneous and fast integrating films are obtained with a disintegration time of 35±2 s and 45± 6 s. As the disintegration time is not specified for ODFs, the disintegration time requirements for ODTs (see above) might be adopted for ODFs. The developed ODFs show a fast drug release profile with enhanced solubility of the API Loratadine in simulated saliva (pH 6.7) - faster than pure API (figures 2a and 2b).

Conclusion: The obtained ODMTs and ODFs meet the requirements of Ph. Eur. for the disintegration time of ODTs and fast drug release is achieved for both dosage forms. ODFs of the drug Loratadine may offer enhanced therapeutic benefits for children. Due to their potential for age-tailored API doses by varying thickness and shapes, they offer an interesting potential for personalized and age-appropriate dosages.

References: 1. Classification of Loratadine Based on Biopharmaceutics Drug Classification Concept and Possible in Vitro-in Vivo Correlation, Khan et al., Biol. Pharm. Bull 27(10) 1630-1635 (2004)

Figure 1: Orodispersible Loratadine mini-tablet (ODTM, 3 mm)

Figure 2a: Dissolution profile of 2.5 mg Loratadine ODF vs. pure API

Figure 2b: Dissolution profile of 5 mg Loratadine ODF vs. pure API